ES2575984T3 - Stable formulations of peptides containing an acylated GLP-1 analogue and a basal insulin - Google Patents

Stable formulations of peptides containing an acylated GLP-1 analogue and a basal insulin Download PDF

Info

Publication number
ES2575984T3
ES2575984T3 ES05803458.8T ES05803458T ES2575984T3 ES 2575984 T3 ES2575984 T3 ES 2575984T3 ES 05803458 T ES05803458 T ES 05803458T ES 2575984 T3 ES2575984 T3 ES 2575984T3
Authority
ES
Spain
Prior art keywords
basal insulin
pharmaceutical composition
analogue
insulin
composition according
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
ES05803458.8T
Other languages
Spanish (es)
Inventor
Svend Ludvigsen
Morten Schlein
Tine Elisabeth Gottschalk BØVING
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novo Nordisk AS
Original Assignee
Novo Nordisk AS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from PCT/DK2005/000589 external-priority patent/WO2006029634A2/en
Application filed by Novo Nordisk AS filed Critical Novo Nordisk AS
Application granted granted Critical
Publication of ES2575984T3 publication Critical patent/ES2575984T3/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/62—Insulins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/26—Glucagons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/28—Insulins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Diabetes (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Endocrinology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Molecular Biology (AREA)
  • Immunology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Biochemistry (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Toxicology (AREA)
  • Dermatology (AREA)
  • Emergency Medicine (AREA)
  • Child & Adolescent Psychology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)
  • Peptides Or Proteins (AREA)

Abstract

Una composición farmacéutica estable al almacenamiento que contiene un análogo de GLP-1 acilado y una insulina basal, un conservante farmacéuticamente aceptable, un surfactante no iónico a una concentración entre 10 mg/L y 500 mg/L, y opcionalmente un modificador de la tonicidad farmacéuticamente aceptable, donde dicha composición tiene un pH en el intervalo entre 7.0 y 8.5, donde dicho análogo de GLP-1 acilado es Arg34, Lys26(Nε-(γ- Glu(Nα-hexadecanoil)))-GLP-1(7-37) y dicha insulina basal es NεB29-tetradecanoil des(B30) insulina humana o NεB29- (Nα-(HOOC(CH2)14CO)-γ-Glu) desB30 insulina humana.A storage stable pharmaceutical composition containing an acylated GLP-1 analogue and a basal insulin, a pharmaceutically acceptable preservative, a non-ionic surfactant at a concentration between 10 mg / L and 500 mg / L, and optionally a tonicity modifier pharmaceutically acceptable, wherein said composition has a pH in the range between 7.0 and 8.5, where said acylated GLP-1 analog is Arg34, Lys26 (Nε- (γ-Glu (Nα-hexadecanoyl))) - GLP-1 (7- 37) and said basal insulin is NεB29-tetradecanoyl des (B30) human insulin or NεB29- (Nα- (HOOC (CH2) 14CO) -γ-Glu) desB30 human insulin.

Description

imagen1image 1

imagen2image2

imagen3image3

imagen4image4

imagen5image5

imagen6image6

5 5

10 10

15 fifteen

20 twenty

25 25

30 30

35 35

40 40

45 Four. Five

50 fifty

55 55

60 60

Una realización de la invención comprende una composición farmacéutica según cualquiera de las realizaciones anteriores, que contiene poloxámero 188 y polisorbato 20 o tween 80. An embodiment of the invention comprises a pharmaceutical composition according to any of the above embodiments, containing poloxamer 188 and polysorbate 20 or tween 80.

Una realización de la invención comprende una composición farmacéutica según cualquiera de las realizaciones previas, en la que el pH está en el intervalo entre 7.4 y 8.0. An embodiment of the invention comprises a pharmaceutical composition according to any of the previous embodiments, wherein the pH is in the range between 7.4 and 8.0.

Una realización de la invención comprende una composición farmacéutica según cualquiera de las realizaciones previas, que contiene un tampón que es un tampón de fosfato. An embodiment of the invention comprises a pharmaceutical composition according to any of the previous embodiments, which contains a buffer that is a phosphate buffer.

Una realización de la invención comprende una composición farmacéutica según cualquiera de las realizaciones anteriores, que contiene un tampón que es un tampón zwitteriónico. An embodiment of the invention comprises a pharmaceutical composition according to any of the above embodiments, which contains a buffer that is a zwitterionic buffer.

Una realización de la invención comprende una composición farmacéutica según la realización anterior, en la que el tampón se elige del grupo que consiste en glicilglicina, TRIS, bicina, HEPES, MOBS, MOPS, TES y sus mezclas. An embodiment of the invention comprises a pharmaceutical composition according to the previous embodiment, wherein the buffer is selected from the group consisting of glycylglycine, TRIS, bicin, HEPES, MOBS, MOPS, TES and mixtures thereof.

Una realización de la invención comprende una composición farmacéutica según cualquiera de las realizaciones previas, en la que el modificador de la tonicidad se elige del grupo que consiste en glicerol, propilenglicol y manitol. An embodiment of the invention comprises a pharmaceutical composition according to any of the previous embodiments, wherein the tonicity modifier is selected from the group consisting of glycerol, propylene glycol and mannitol.

Una realización de la invención comprende una composición farmacéutica según cualquiera de las realizaciones previas, en la que el conservante se elige del grupo que consiste en fenol, m-cresol, p-hidroxibenzoato de metilo, phidroxibenzoato de propilo, 2-fenoxietanol, p-hidroxibenzoato de butilo, 2-feniletanol, alcohol bencílico, clorobutanol, tiomersal y sus mezclas. An embodiment of the invention comprises a pharmaceutical composition according to any of the previous embodiments, wherein the preservative is selected from the group consisting of phenol, m-cresol, methyl p-hydroxybenzoate, propyl phydroxybenzoate, 2-phenoxyethanol, p- butyl hydroxybenzoate, 2-phenylethanol, benzyl alcohol, chlorobutanol, thiomersal and mixtures thereof.

Una realización de la invención comprende una composición farmacéutica según cualquiera de las realizaciones previas, en la que la concentración de dicho análogo de GLP-1 acilado está en el intervalo entre 0.1 mg/ml y 25 mg/ml, en el intervalo entre 1 mg/ml y 25 mg/ml, en el intervalo entre 2 mg/ml y 15 mg/ml, en el intervalo entre 3 mg/ml y 10 mg/ml o en el intervalo entre 3 mg/ml y 5 mg/ml. An embodiment of the invention comprises a pharmaceutical composition according to any of the previous embodiments, wherein the concentration of said acylated GLP-1 analog is in the range between 0.1 mg / ml and 25 mg / ml, in the range between 1 mg / ml and 25 mg / ml, in the range between 2 mg / ml and 15 mg / ml, in the range between 3 mg / ml and 10 mg / ml or in the range between 3 mg / ml and 5 mg / ml.

Una realización de la invención comprende una composición farmacéutica según cualquiera de las realizaciones anteriores, en la que la concentración de dicho análogo de GLP-1 acilado en la composición farmacéutica es entre 5 µg/mL y 10 mg/mL, entre 5 µg/mL y 5 mg/mL, entre 5 µg/mL y 5 mg/mL, entre 0.1 mg/mL y 3 mg/mL o entre 0.2 mg/mL y 1 mg/mL. An embodiment of the invention comprises a pharmaceutical composition according to any of the above embodiments, wherein the concentration of said acylated GLP-1 analog in the pharmaceutical composition is between 5 µg / mL and 10 mg / mL, between 5 µg / mL and 5 mg / mL, between 5 µg / mL and 5 mg / mL, between 0.1 mg / mL and 3 mg / mL or between 0.2 mg / mL and 1 mg / mL.

Una realización de la invención comprende una composición farmacéutica según la realización anterior, en la que dicha insulina basal es NεB29-tetradecanoil des(B30) insulina humana o NεB29-(Nα-(HOOC(CH2)14CO)-γ-Glu) desB30 insulina humana. An embodiment of the invention comprises a pharmaceutical composition according to the previous embodiment, wherein said basal insulin is NεB29-tetradecanoyl des (B30) human insulin or NεB29- (Nα- (HOOC (CH2) 14CO) -γ-Glu) desB30 insulin human

Una realización de la invención comprende una composición farmacéutica según cualquiera de las realizaciones previas, en la que la concentración de dicho insulina basal está en el intervalo entre 1.6 mg/mL y 5.6 mg/mL, o entre An embodiment of the invention comprises a pharmaceutical composition according to any of the previous embodiments, wherein the concentration of said basal insulin is in the range between 1.6 mg / mL and 5.6 mg / mL, or between

2.6 mg/mL y 4.6 mg/mL, o entre 3.2 mg/mL y 4.0 mg/mL. 2.6 mg / mL and 4.6 mg / mL, or between 3.2 mg / mL and 4.0 mg / mL.

Una realización de la invención comprende un método para la preparación de una composición farmacéutica según cualquiera de las realizaciones previas, que consiste en disolver dicho péptido insulinotrópico y mezclar el conservante y el modificador de la tonicidad, y finalmente mezclar la insulina basal disuelta. An embodiment of the invention comprises a method for the preparation of a pharmaceutical composition according to any of the previous embodiments, which consists in dissolving said insulinotropic peptide and mixing the preservative and the tonicity modifier, and finally mixing the dissolved basal insulin.

Una realización de la invención comprende un método para la preparación de una composición farmacéutica según cualquiera de las realizaciones anteriores, que consiste en disolver o suspender dicha insulina basal y mezclar el conservante y el modificador de la tonicidad, y finalmente mezclar el péptido insulinotrópico disuelto. An embodiment of the invention comprises a method for the preparation of a pharmaceutical composition according to any of the above embodiments, which consists in dissolving or suspending said basal insulin and mixing the preservative and the tonicity modifier, and finally mixing the dissolved insulinotropic peptide.

Una realización de la invención comprende el uso de la composición farmacéutica según cualquiera de las realizaciones anteriores para la preparación de un medicamento destinado al tratamiento de la hiperglucemia que consiste en la administración parenteral de dicho tratamiento a un mamífero que lo necesita. An embodiment of the invention comprises the use of the pharmaceutical composition according to any of the previous embodiments for the preparation of a medicament for the treatment of hyperglycemia consisting of parenteral administration of said treatment to a mammal in need thereof.

Una realización de la invención comprende el uso de la composición farmacéutica según cualquiera de las realizaciones anteriores para la preparación de un medicamento destinado al tratamiento de la obesidad, la deficiencia de células beta, IGT o dislipidemia, que consiste en la administración parenteral de dicho tratamiento a un mamífero que lo necesita. An embodiment of the invention comprises the use of the pharmaceutical composition according to any of the above embodiments for the preparation of a medicament for the treatment of obesity, beta cell deficiency, IGT or dyslipidemia, which consists of parenteral administration of said treatment. to a mammal that needs it.

El uso de excipientes como conservantes, agentes isotónicos y surfactantes en composiciones farmacéuticas es bien conocido por los expertos. Por conveniencia se hace referencia a Remington: The Science and Practice of Pharmacy, 19ª Edición, 1995. The use of excipients as preservatives, isotonic agents and surfactants in pharmaceutical compositions is well known to the experts. For convenience, reference is made to Remington: The Science and Practice of Pharmacy, 19th Edition, 1995.

El péptido semejante al glucagón parental se puede producir por síntesis peptídica, por ejemplo síntesis peptídica en fase sólida empleando química de t-Boc o F-Moc u otras técnicas bien establecidas. El péptido semejante al The parental glucagon-like peptide can be produced by peptide synthesis, for example solid phase peptide synthesis using t-Boc or F-Moc chemistry or other well established techniques. The peptide similar to

8 8

imagen7image7

imagen8image8

Cada corrida se inició incubando la placa a la temperatura del ensayo durante 10 min. La placa se midió cada 20 minutos durante normalmente 45 horas. Entre cada medición, la placa se agitó y se calentó como se describe. Each run was started by incubating the plate at the test temperature for 10 min. The plate was measured every 20 minutes for normally 45 hours. Between each measurement, the plate was stirred and heated as described.

Manipulación de los datos Data manipulation

5 Los puntos de medición se guardaron en formato Excel de Microsoft para el procesamiento posterior, y el trazado y el ajuste de la curva se realizaron usando GraphPad Prism. La emisión de fondo de ThT en ausencia de fibrillas fue insignificante. Los puntos de datos son habitualmente una media de ocho muestras y se muestran con barras de error de desviación estándar. Sólo los datos obtenidos en el mismo experimento (es decir, las muestras de la misma 5 The measurement points were saved in Microsoft Excel format for further processing, and plotting and curve adjustment were performed using GraphPad Prism. The background emission of ThT in the absence of fibrils was insignificant. Data points are usually an average of eight samples and are shown with standard deviation error bars. Only the data obtained in the same experiment (i.e. the samples of the same

10 placa) se presentan en el mismo gráfico asegurando una medida relativa de la fibrilación entre muestras individuales de un ensayo, en vez de la comparación entre ensayos diferentes. El conjunto de datos se puede ajustar a la ecuación (1). Sin embargo, puesto que en este caso las curvas sigmoidales completas generalmente no se alcanzan durante el tiempo de la medición, el grado de fibrilación se expresa como la florescencia de ThT a diversos tiempos, calculada como la media de las ocho muestras y mostrada con la desviación estándar 10 plate) are presented on the same graph ensuring a relative measure of fibrillation between individual samples of one test, rather than the comparison between different tests. The data set can be adjusted to equation (1). However, since in this case the complete sigmoidal curves are generally not reached during the measurement time, the degree of fibrillation is expressed as the ThT fluorescence at various times, calculated as the average of the eight samples and shown with the standard deviation

15 Los ejemplos siguientes ilustran la invención. The following examples illustrate the invention.

Ejemplo 1 Example 1

20 Un ejemplo de una mezcla de una insulina basal y liraglutida podría ser una preparación de detemir 1.2 mM y liraglutida 1.2 mM en una formulación que contenga acetato de Zn 0.5 mM, tampón de fosfato de sodio 8 mM, cloruro de sodio 20 mM, fenol 60 mM y 14 mg/ml de propilenglicol a pH 7.7 con 200 ppm de polisorbato 20. An example of a mixture of a basal insulin and liraglutide could be a preparation of 1.2 mM detemir and 1.2 mM liraglutide in a formulation containing 0.5 mM Zn acetate, 8 mM sodium phosphate buffer, 20 mM sodium chloride, phenol 60 mM and 14 mg / ml propylene glycol at pH 7.7 with 200 ppm polysorbate 20.

Ejemplo 2. Example 2

25 Otro ejemplo de una mezcla de una insulina basal y liraglutida podría ser una preparación de detemir 2.4 mM y liraglutida 3.0 mM en una formulación que contenga acetato de Zn 1.2 mM, tampón de fosfato de sodio 8 mM, cloruro de sodio 10 mM, fenol 20 mM, m-cresol 20 mM y 14 mg/ml de propilenglicol a pH 7.7 con 300 ppm de polisorbato 20. Another example of a mixture of a basal insulin and liraglutide could be a preparation of 2.4 mM detemir and 3.0 mM liraglutide in a formulation containing 1.2 mM Zn acetate, 8 mM sodium phosphate buffer, 10 mM sodium chloride, phenol 20 mM, 20 mM m-cresol and 14 mg / ml propylene glycol at pH 7.7 with 300 ppm polysorbate 20.

30 Ejemplo 3 30 Example 3

Otro ejemplo de una mezcla de una insulina basal y liraglutida podría ser una preparación de detemir 1.2 mM y liraglutida 1.67 mM en una formulación que contenga acetato de Zn 0.8 mM, tampón de glicilglicina 8 mM, cloruro de Another example of a mixture of a basal insulin and liraglutide could be a preparation of 1.2 mM detemir and 1.67 mM liraglutide in a formulation containing 0.8 mM Zn acetate, 8 mM glycylglycine buffer, chloride

35 sodio 10 mM, fenol 20 mM, m-cresol 20 mM y 14 mg/ml de propilenglicol a pH 7.7 con 100 ppm de poloxámero 188. 10 mM sodium, 20 mM phenol, 20 mM m-cresol and 14 mg / ml propylene glycol at pH 7.7 with 100 ppm poloxamer 188.

Ejemplo 4 Example 4

Otro ejemplo de una mezcla de una insulina basal y liraglutida podría ser una preparación de detemir 2.4 mM y Another example of a mixture of a basal insulin and liraglutide could be a 2.4 mM detemir preparation and

40 liraglutida 1.2 mM en una formulación que contenga acetato de Zn 2.0 mM, tampón de fosfato de sodio 8 mM, cloruro de sodio 10 mM, fenol 20 mM, m-cresol 20 mM y 14 mg/ml de propilenglicol a pH 7.7 con 300 ppm de polisorbato 20. 40 liraglutide 1.2 mM in a formulation containing 2.0 mM Zn acetate, 8 mM sodium phosphate buffer, 10 mM sodium chloride, 20 mM phenol, 20 mM m-cresol and 14 mg / ml propylene glycol at pH 7.7 with 300 ppm polysorbate 20.

Ejemplo 5 Example 5

45 Mezclas de detemir 2.4 mM y liraglutida 1.2 mM en una formulación que contiene acetato de Zn 1.2 mM, glicilglicina 5 mM, cloruro de sodio 20 mM, fenol 60 mM y 14 mg/ml de propilenglicol a pH 7.7 (figura 1, diamantes) y la misma formulación pero con el agregado de 300 ppm de polisorbato 20 (tween 20). La fluorescencia de ThT se siguió mediante el procedimiento general descrito antes. Esta mezcla también se muestra con el agregado de 200 ppm de 45 Mixtures of 2.4 mM detemir and 1.2 mM liraglutide in a formulation containing 1.2 mM Zn acetate, 5 mM glycylglycine, 20 mM sodium chloride, 60 mM phenol and 14 mg / ml propylene glycol at pH 7.7 (Figure 1, diamonds) and the same formulation but with the addition of 300 ppm of polysorbate 20 (tween 20). ThT fluorescence was followed by the general procedure described above. This mixture is also shown with the 200 ppm aggregate of

50 polisorbato-20 o 1000 ppm de poloxámero-188. 50 polysorbate-20 or 1000 ppm poloxamer-188.

Ejemplo 6 Example 6

Mezclas de detemir 2.4 mM y liraglutida 1.2 mM en una formulación que contiene acetato de Zn 1.2 mM, glicilglicina Mixtures of 2.4 mM detemir and 1.2 mM liraglutide in a formulation containing 1.2 mM Zn acetate, glycylglycine

55 5 mM, cloruro de sodio 20 mM, fenol 60 mM y 14 mg/ml de propilenglicol a pH 7.7 (figura 2, diamantes) y la misma formulación pero con el agregado de 300 ppm de polisorbato 20 (tween 20) a tres valores de pH diferentes, triángulos (fig. 2) a pH 7.4, cuadrados (fig. 2) a pH 7.7 y círculos (fig. 2) a pH 8.1. La fluorescencia de ThT se siguió mediante el procedimiento general descrito antes. 5 mM, 20 mM sodium chloride, 60 mM phenol and 14 mg / ml propylene glycol at pH 7.7 (figure 2, diamonds) and the same formulation but with the addition of 300 ppm polysorbate 20 (tween 20) to three values of different pH, triangles (fig. 2) at pH 7.4, squares (fig. 2) at pH 7.7 and circles (fig. 2) at pH 8.1. ThT fluorescence was followed by the general procedure described above.

60 Ejemplo 7 60 Example 7

Mezclas de detemir 2.4 mM y liraglutida 2.4 mM en una formulación que contiene acetato de Zn 1.2 mM, tampón de fosfato de sodio 8 mM, cloruro de sodio 20 mM, fenol 60 mM y 14 mg/ml de propilenglicol a pH 7.7 (figura 3, cuadrados) y la misma formulación pero con el agregado de 300 ppm de polisorbato 20 que se muestra con Mixtures of 2.4 mM detemir and 2.4 mM liraglutide in a formulation containing 1.2 mM Zn acetate, 8 mM sodium phosphate buffer, 20 mM sodium chloride, 60 mM phenol and 14 mg / ml propylene glycol at pH 7.7 (Figure 3 , squares) and the same formulation but with the 300 ppm polysorbate 20 aggregate shown with

11 eleven

símbolos de estrellas (fig. 3). La fluorescencia de ThT se siguió mediante el procedimiento general descrito antes. Star symbols (fig. 3). ThT fluorescence was followed by the general procedure described above.

Ejemplo 8 Example 8

5 Mezclas de detemir 2.4 mM y liraglutida 2.4 mM en una formulación que contiene acetato de Zn 1.2 mM, tampón de fosfato de sodio 8 mM, cloruro de sodio 20 mM, fenol 60 mM y 14 mg/ml de propilenglicol a pH 7.7 (figura 4, cuadrados) y la misma formulación pero con el agregado de 2 niveles de poloxámero 188, 100 ppm que se muestran con cruces (fig. 4) y 500 ppm con triángulos (fig. 4). La fluorescencia de ThT se siguió mediante el procedimiento general descrito antes. 5 Mixtures of 2.4 mM detemir and 2.4 mM liraglutide in a formulation containing 1.2 mM Zn acetate, 8 mM sodium phosphate buffer, 20 mM sodium chloride, 60 mM phenol and 14 mg / ml propylene glycol at pH 7.7 (Figure 4, squares) and the same formulation but with the addition of 2 levels of poloxamer 188, 100 ppm shown with crosses (fig. 4) and 500 ppm with triangles (fig. 4). ThT fluorescence was followed by the general procedure described above.

10 Ejemplo 9 10 Example 9

La formulación A consiste en: NεB29-(Nα-(HOOC(CH2)14CO)-γ-Glu) desB30 insulina humana 0.6 mM, Zn2+ 0.3 mM (correspondiente a 3 iones de Zn2+ por hexámero de insulina), fenol 60 mM, 14 mg/ml de propilenglicol, fosfato 5 mM Formulation A consists of: NεB29- (Nα- (HOOC (CH2) 14CO) -γ-Glu) desB30 human insulin 0.6 mM, Zn2 + 0.3 mM (corresponding to 3 ions of Zn2 + per hexamer of insulin), 60 mM phenol, 14 mg / ml propylene glycol, 5 mM phosphate

15 de pH 7.7 y liraglutida 1.2 mM. La mezcla comienza a formar fibrillas con un tiempo de retraso corto de aproximadamente una hora. Sin embargo, el agregado de 200 ppm de polisorbato-20 o 1000 ppm de poloxámero188 prolonga el tiempo de retraso a más de 30 horas. (fig. 5). 15 pH 7.7 and 1.2 mM liraglutide. The mixture begins to form fibrils with a short delay time of approximately one hour. However, the addition of 200 ppm of polysorbate-20 or 1000 ppm of poloxamer188 prolongs the delay time to more than 30 hours. (fig. 5).

Ejemplo 10 Example 10

20 La formulación B consiste en: NεB29-(Nα-(HOOC(CH2)14CO)-γ-Glu) desB30 insulina humana 0.6 mM, Zn2+ 0.5 mM (correspondiente a 5 iones de Zn2+ por hexámero de insulina), fenol 60 mM, 14 mg/ml de propilenglicol, fosfato 5 mM de pH 7.7 y liraglutida 1.2 mM. Se muestra la misma formulación con el agregado de 500 ppm de polisorbato-20 y de 2000 ppm de poloxámero-188 (fig 6). Formulation B consists of: NεB29- (Nα- (HOOC (CH2) 14CO) -γ-Glu) desB30 human insulin 0.6 mM, Zn2 + 0.5 mM (corresponding to 5 ions of Zn2 + per hexamer of insulin), 60 mM phenol, 14 mg / ml propylene glycol, 5 mM phosphate pH 7.7 and 1.2 mM liraglutide. The same formulation is shown with the addition of 500 ppm polysorbate-20 and 2000 ppm poloxamer-188 (fig 6).

25 25

12 12

Claims (1)

imagen1image 1
ES05803458.8T 2004-11-12 2005-11-11 Stable formulations of peptides containing an acylated GLP-1 analogue and a basal insulin Expired - Lifetime ES2575984T3 (en)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
DKPA200401752 2004-11-12
DK200401752 2004-11-12
EP05104049 2005-05-13
EP05104049 2005-05-13
PCT/DK2005/000589 WO2006029634A2 (en) 2004-09-17 2005-09-19 Pharmaceutical compositions containing insulin and insulinotropic peptide
DK200500589 2005-09-19
PCT/EP2005/055916 WO2006051103A2 (en) 2004-11-12 2005-11-11 Stable formulations of peptides

Publications (1)

Publication Number Publication Date
ES2575984T3 true ES2575984T3 (en) 2016-07-04

Family

ID=39560968

Family Applications (1)

Application Number Title Priority Date Filing Date
ES05803458.8T Expired - Lifetime ES2575984T3 (en) 2004-11-12 2005-11-11 Stable formulations of peptides containing an acylated GLP-1 analogue and a basal insulin

Country Status (5)

Country Link
US (1) US20090011976A1 (en)
EP (1) EP1814581B1 (en)
JP (1) JP5248113B2 (en)
ES (1) ES2575984T3 (en)
WO (1) WO2006051103A2 (en)

Families Citing this family (64)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003002136A2 (en) * 2001-06-28 2003-01-09 Novo Nordisk A/S Stable formulation of modified glp-1
CA2531988C (en) 2003-08-05 2016-06-28 Novo Nordisk A/S Novel insulin derivatives
DK3300721T4 (en) * 2003-11-20 2025-03-03 Novo Nordisk As PROPYLENE GLYCOL-CONTAINING PEPTIDE FORMULATIONS WHICH ARE OPTIMAL FOR MANUFACTURING AND FOR USE IN INJECTION DEVICES
WO2006037810A2 (en) 2004-10-07 2006-04-13 Novo Nordisk A/S Protracted glp-1 compounds
US8030273B2 (en) 2004-10-07 2011-10-04 Novo Nordisk A/S Protracted exendin-4 compounds
ES2371361T3 (en) 2005-12-28 2011-12-30 Novo Nordisk A/S COMPOSITIONS THAT INCLUDE AN INSULIN ACILADA AND ZINC AND METHOD OF PRODUCTION OF SUCH COMPOSITIONS.
WO2008023050A1 (en) 2006-08-25 2008-02-28 Novo Nordisk A/S Acylated exendin-4 compounds
WO2008087121A1 (en) * 2007-01-17 2008-07-24 Merz Pharma Gmbh & Co. Kgaa Use of a surfactant for the preparation of a formulation for the treatment of adipose dieseases
JP5552046B2 (en) 2007-06-13 2014-07-16 ノボ・ノルデイスク・エー／エス Pharmaceutical preparation containing an insulin derivative
BRPI0820535B8 (en) * 2007-11-16 2021-05-25 Novo Nordisk As pharmaceutical compositions containing insulin and an insulinotropic peptide
RS59913B1 (en) * 2008-10-17 2020-03-31 Sanofi Aventis Deutschland Combination of an insulin and a glp-1 agonist
DE102008053048A1 (en) * 2008-10-24 2010-04-29 Sanofi-Aventis Deutschland Gmbh Medicament, useful e.g. for treating diabetes, controlling fasting, postprandial or postabsorptive blood glucose concentration in diabetic patients and improving glucose tolerance, comprises insulin and glucagon-like peptide-1 agonist
JP4959005B2 (en) 2008-10-30 2012-06-20 ノボ・ノルデイスク・エー／エス Treatment of diabetes mellitus with insulin injections less than daily injection frequency
CN102596175A (en) 2009-07-06 2012-07-18 赛诺菲-安万特德国有限公司 Aqueous insulin preparations containing methionine
MY180661A (en) 2009-11-13 2020-12-04 Sanofi Aventis Deutschland Pharmaceutical composition comprising a glp-1 agonist, an insulin and methionine
PT3345593T (en) 2009-11-13 2023-11-27 Sanofi Aventis Deutschland Pharmaceutical composition comprising despro36exendin-4(1-39)-lys6-nh2 and methionine
PL2611458T3 (en) 2010-08-30 2017-02-28 Sanofi-Aventis Deutschland Gmbh Use of ave0010 for the manufacture of a medicament for the treatment of diabetes mellitus type 2
DK2632478T3 (en) 2010-10-27 2019-10-07 Novo Nordisk As TREATMENT OF DIABETES MELITUS USING INSULIN INJECTIONS SUBMITTED AT VARIOUS INJECTION INTERVALS
US9821032B2 (en) 2011-05-13 2017-11-21 Sanofi-Aventis Deutschland Gmbh Pharmaceutical combination for improving glycemic control as add-on therapy to basal insulin
DK2741765T3 (en) 2011-08-10 2016-06-13 Adocia Injectable solution of at least one type of basal insulin
AR087693A1 (en) 2011-08-29 2014-04-09 Sanofi Aventis Deutschland PHARMACEUTICAL COMBINATION FOR USE IN GLUCEMIC CONTROL IN PATIENTS WITH TYPE 2 DIABETES
TWI559929B (en) 2011-09-01 2016-12-01 Sanofi Aventis Deutschland Pharmaceutical composition for use in the treatment of a neurodegenerative disease
US9198971B2 (en) 2012-01-09 2015-12-01 Adocia Injectable solution at pH 7 comprising at least one basal insulin the pI of which is between 5.8 and 8.5 and a substituted co-polyamino acid
CN104411322B (en) * 2012-05-08 2017-05-24 诺和诺德股份有限公司 Diacylated GLP‑1 Derivatives
US9624287B2 (en) 2012-07-17 2017-04-18 Case Western Reserve University O-linked carbohydrate-modified insulin analogues
EP2877200B1 (en) * 2012-07-17 2019-05-08 Case Western Reserve University O-linked carbohydrate-modified insulin analogues
AR092862A1 (en) 2012-07-25 2015-05-06 Hanmi Pharm Ind Co Ltd LIQUID FORMULATION OF PROLONGED ACTION INSULIN AND AN INSULINOTROPIC PEPTIDE AND PREPARATION METHOD
US20150314003A2 (en) 2012-08-09 2015-11-05 Adocia Injectable solution at ph 7 comprising at least one basal insulin the isoelectric point of which is between 5.8 and 8.5 and a hydrophobized anionic polymer
UA116217C2 (en) 2012-10-09 2018-02-26 Санофі Exendin-4 derivatives as dual glp1/glucagon agonists
AU2013366692B2 (en) 2012-12-21 2017-11-23 Sanofi Dual GLP1/GIP or trigonal GLP1/GIP/Glucagon agonists
TWI780236B (en) 2013-02-04 2022-10-11 法商賽諾菲公司 Stabilized pharmaceutical formulations of insulin analogues and/or insulin derivatives
EP2991672A1 (en) 2013-04-30 2016-03-09 Novo Nordisk A/S Novel administration regime
EP3080152A1 (en) 2013-12-13 2016-10-19 Sanofi Non-acylated exendin-4 peptide analogues
WO2015086733A1 (en) 2013-12-13 2015-06-18 Sanofi Dual glp-1/glucagon receptor agonists
EP3080154B1 (en) 2013-12-13 2018-02-07 Sanofi Dual glp-1/gip receptor agonists
WO2015086728A1 (en) 2013-12-13 2015-06-18 Sanofi Exendin-4 peptide analogues as dual glp-1/gip receptor agonists
MX2016008979A (en) 2014-01-09 2016-10-04 Sanofi Sa Stabilized pharmaceutical formulations of insulin analogues and/or insulin derivatives.
MX2016008978A (en) 2014-01-09 2016-10-04 Sanofi Sa Stabilized glycerol free pharmaceutical formulations of insulin analogues and/or insulin derivatives.
BR112016015851A2 (en) 2014-01-09 2017-08-08 Sanofi Sa STABILIZED PHARMACEUTICAL FORMULATIONS OF INSULIN ASPART
TW201625670A (en) 2014-04-07 2016-07-16 賽諾菲公司 Dual GLP-1/glucagon receptor agonists derived from EXENDIN-4
TW201625668A (en) 2014-04-07 2016-07-16 賽諾菲公司 Exendin-4 derivatives as peptidic dual GLP-1/glucagon receptor agonists
TW201625669A (en) 2014-04-07 2016-07-16 賽諾菲公司 Peptidic dual GLP-1/glucagon receptor agonists derived from Exendin-4
US9932381B2 (en) 2014-06-18 2018-04-03 Sanofi Exendin-4 derivatives as selective glucagon receptor agonists
EP3229828B1 (en) 2014-12-12 2023-04-05 Sanofi-Aventis Deutschland GmbH Insulin glargine/lixisenatide fixed ratio formulation
DK3244878T3 (en) 2015-01-12 2022-10-17 Enteris Biopharma Inc Solid oral formulations
TWI748945B (en) 2015-03-13 2021-12-11 德商賽諾菲阿凡提斯德意志有限公司 Treatment type 2 diabetes mellitus patients
TW201705975A (en) 2015-03-18 2017-02-16 賽諾菲阿凡提斯德意志有限公司 Treatment of type 2 diabetes mellitus patients
AR105319A1 (en) 2015-06-05 2017-09-27 Sanofi Sa PROPHARMS THAT INCLUDE A DUAL AGONIST GLU-1 / GLUCAGON CONJUGATE HIALURONIC ACID CONNECTOR
TW201706291A (en) 2015-07-10 2017-02-16 賽諾菲公司 New EXENDIN-4 derivatives as selective peptidic dual GLP-1/glucagon receptor agonists
GB201607918D0 (en) * 2016-05-06 2016-06-22 Arecor Ltd Novel formulations
WO2018055539A1 (en) 2016-09-22 2018-03-29 Wockhardt Limited Pharmaceutical composition containing buffered insulin glargine and glp-1 analogue
JP2019529506A (en) 2016-09-29 2019-10-17 アレコル リミテッド New formulation
KR102665710B1 (en) 2017-08-24 2024-05-14 노보 노르디스크 에이/에스 GLP-1 composition and its uses
US12357562B2 (en) 2018-04-04 2025-07-15 Arecor Limited Injection pen system for the delivery of an insulin compound
TWI705820B (en) 2018-06-22 2020-10-01 美商美國禮來大藥廠 Gip/glp1 agonist compositions
US10335464B1 (en) 2018-06-26 2019-07-02 Novo Nordisk A/S Device for titrating basal insulin
WO2020190591A1 (en) * 2019-03-15 2020-09-24 Eli Lilly And Company Preserved formulations
US12343383B2 (en) 2019-07-12 2025-07-01 Novo Nordisk A/S High concentration insulin formulation
WO2021142733A1 (en) * 2020-01-16 2021-07-22 Shanghai Benemae Pharmaceutical Corporation Combinational therapy comprising glp-1 and/or glp-1 analogs, and insulin and/or insulin analogs
CN115397455A (en) * 2020-01-16 2022-11-25 上海仁会生物制药股份有限公司 GLP-1 dosing regimens
JP7761567B2 (en) 2020-02-18 2025-10-28 ノヴォ ノルディスク アー／エス Pharmaceutical preparations
EP4281039A2 (en) 2021-01-25 2023-11-29 Mylan Ireland Limited Pharmaceutical glp peptide compositions and methods of preparation thereof
US20230053812A1 (en) * 2021-07-27 2023-02-23 Aurobindo Pharma Ltd Stable peptide formulations for oral use
US11981936B1 (en) 2023-09-29 2024-05-14 New England Biolabs, Inc. TelA variants, compositions, and methods

Family Cites Families (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6011007A (en) * 1993-09-17 2000-01-04 Novo Nordisk A/S Acylated insulin
GB9409496D0 (en) * 1994-05-12 1994-06-29 London Health Ass Method for improving glycaemic control in diabetes
US20010041786A1 (en) * 1995-06-07 2001-11-15 Mark L. Brader Stabilized acylated insulin formulations
US6458924B2 (en) * 1996-08-30 2002-10-01 Novo Nordisk A/S Derivatives of GLP-1 analogs
US7235627B2 (en) * 1996-08-30 2007-06-26 Novo Nordisk A/S Derivatives of GLP-1 analogs
US6268343B1 (en) * 1996-08-30 2001-07-31 Novo Nordisk A/S Derivatives of GLP-1 analogs
DE69928006T2 (en) * 1998-12-22 2006-07-13 Eli Lilly And Co., Indianapolis STABILITY LIQUID COMPOSITIONS OF GLUCAGON-SIMILAR PEPTIDE-1
WO2001000223A2 (en) * 1999-06-25 2001-01-04 Minimed Inc. Multiple agent diabetes therapy
EP1076066A1 (en) * 1999-07-12 2001-02-14 Zealand Pharmaceuticals A/S Peptides for lowering blood glucose levels
US6844321B2 (en) * 2000-01-31 2005-01-18 Novo Nordisk A/S Crystallization of a GLP-1 analogue
EP1432430A4 (en) * 2001-08-28 2006-05-10 Lilly Co Eli Pre-mixes of glp-1 and basal insulin
MXPA04003569A (en) * 2001-10-19 2004-07-23 Lilly Co Eli Biphasic mixtures of glp-1 and insulin.
WO2003059378A2 (en) * 2001-12-29 2003-07-24 Novo Nordisk A/S Combined use of a glp-1 compound and another drug for treating dyslipidemia
JP5599543B2 (en) * 2002-05-07 2014-10-01 ノヴォ ノルディスク アー／エス Soluble formulation containing monomeric insulin and acylated insulin
WO2004050115A2 (en) * 2002-12-03 2004-06-17 Novo Nordisk A/S Combination treatment using exendin-4 and thiazolidinediones
US20060247167A1 (en) * 2003-09-01 2006-11-02 Novo Nordisk A/S Stable formulations of peptides
US20060287221A1 (en) * 2003-11-13 2006-12-21 Novo Nordisk A/S Soluble pharmaceutical compositions for parenteral administration comprising a GLP-1 peptide and an insulin peptide of short time action for treatment of diabetes and bulimia
ES2373660T3 (en) * 2003-11-13 2012-02-07 Novo Nordisk A/S PHARMACEUTICAL COMPOSITION THAT INCLUDES AN INSULINOTROPIC GLP-1 ANALOG (7-37), ASP INSULIN (B28) AND A TENSIOACTIVE.
US7192919B2 (en) * 2004-01-07 2007-03-20 Stelios Tzannis Sustained release compositions for delivery of pharmaceutical proteins
MX2007005521A (en) * 2004-11-12 2007-05-18 Novo Nordisk As Stable formulations of insulinoptropic peptides.
ES2371361T3 (en) * 2005-12-28 2011-12-30 Novo Nordisk A/S COMPOSITIONS THAT INCLUDE AN INSULIN ACILADA AND ZINC AND METHOD OF PRODUCTION OF SUCH COMPOSITIONS.
JP5552046B2 (en) * 2007-06-13 2014-07-16 ノボ・ノルデイスク・エー／エス Pharmaceutical preparation containing an insulin derivative

Also Published As

Publication number Publication date
EP1814581A2 (en) 2007-08-08
WO2006051103A2 (en) 2006-05-18
WO2006051103A3 (en) 2006-11-16
EP1814581B1 (en) 2016-03-16
JP2008519807A (en) 2008-06-12
JP5248113B2 (en) 2013-07-31
US20090011976A1 (en) 2009-01-08

Similar Documents

Publication Publication Date Title
ES2575984T3 (en) Stable formulations of peptides containing an acylated GLP-1 analogue and a basal insulin
ES2552636T3 (en) Halogen stabilized insulin
ES2533601T3 (en) New composition comprising glucagon
ES2373660T3 (en) PHARMACEUTICAL COMPOSITION THAT INCLUDES AN INSULINOTROPIC GLP-1 ANALOG (7-37), ASP INSULIN (B28) AND A TENSIOACTIVE.
ES2363272T3 (en) FORMULATIONS OF THE PARTIROID HORMONE AND USES OF THE SAME.
ES2399645T3 (en) GLP-1 analog formulations
ES2607003T3 (en) Treatment of diabetes mellitus using insulin injections with an injection frequency less than daily
ES2954180T3 (en) Pharmaceutical formulation comprising an insulin compound
ES2442869T3 (en) Uses of durable formulations of GLP-1 peptides as hypoglycemic
ES2713851T3 (en) Mimetics of calcitonin for the treatment of diseases and disorders
PT1638594E (en) Hip/pap polypeptide composition for use in liver regeneration and for the prevention of liver failure
EA201100180A1 (en) STABILIZED PREPARATION ANTIBODY AGAINST BETA PEPTIDE
BR112013023151A2 (en) interleukin-2 for use in the treatment of autoimmune, immune-related or inflammatory disorder and method for determining whether a regimen or dose of il-2 needs to be modified
ES2969277T3 (en) Compositions in the form of an injectable aqueous solution comprising at least human insulin A21G and a glucagon suppressant with prandial action
PT2349314E (en) FORMULATIONS OF VIO RECYBINANT LIOFILIZADO
ES2973374T3 (en) Stable insulin formulations
ES2548378T3 (en) Aqueous composition containing follicle stimulating hormone
KR20060100428A (en) Propylene Glycol-Containing Peptide Formulations Optimized for Manufacturing and Injection Devices
BRPI0820535B1 (en) PHARMACEUTICAL COMPOSITIONS CONTAINING INSULIN AND AN INSULINOTROPIC PEPTIDE
JP2010539131A (en) A stable formulation of amylin and its analogs
ES2664045T3 (en) Peptides
ES2857749T3 (en) Peptides for the treatment of diabetes
ES2350337T3 (en) STABLE PHARMACEUTICAL COMPOSITION CONTAINING FACTOR VIII.
BR112021003088A2 (en) acylated calcitonin mimetics
ES2759729T3 (en) Animal model for dry eye and methods of use of such animals